It is hypothesized that there is a difference in the peritumoral and tumor related signal abnormality detected by 1.5 tesla (T) versus 3T T2 FLAIR magnet resonance imaging (MRIs). We assessed the difference in radiation treatment gross tumor volumes (GTVs) defined by four investigators for high-grade gliomas as determined using 1.5T vs. 3T MRIs. A total of 23 patients with newly diagnosed, high grade-gliomas were enrolled in this IRB approved prospective trial. All patients underwent a 1.5T and 3T MR scans within a 24-hour period, with no treatment or steroid dose change between scans. The 1.5T study was part of the clinical standard of care and hence was the MR imaging with intravenous gadolinium administration and was used for radiation treatment planning. Gadolinium was not given at 3T imaging. The imaging parameters for T1, T2, and FLAIR sequences were those that are clinically employed at this institution. Image processing and radiation planning was performed using radiation oncology software. MRIs were fused by a designated physicist and were reviewed by a radiation oncologist. GTV delineation was independently performed by 4 experienced investigators: 2 radiation oncologists and 2 neurosurgeons. To decrease inherent biases, investigators contoured 1.5T and 3T MRs separately, with a minimum of 72 hours between contours, blinded to other contours. GTV was defined by the extent of peritumoral edema depicted by high T2 FLAIR signal abnormality. For each patient and investigator the volumes defined by FLAIR images at 1.5 and 3T were determined and the ratio of the volumes (GTV3T/GTV1.5T) were calculated. The mean volume ratios were calculated for each investigator as well as an overall average. To assess the consistency of contours from investigator to investigator, the standard deviations and range of the volumes amongst all investigators were determined for each patient at each field strength. The volumes ratios for each investigator (GTV3T/GTV1.5T) were 0.86 ± 0.20 (range, 0.37-1.03), 0.90 ± 0.20 (range, 0.19-1.08), 0.94 ± 0.18 (range, 0.37-1.14), and 0.98 ± 0.14 (range, 0.66-1.18). One patient was clearly an outlier, with 3T volumes 0.19 to 0.66 that of the 1.5T volumes. The overall GTV3T/GTV1.5Tratio was 0.95 ± 0.19. Excluding the outlier produced an overall GTV3T/GTV1.5T ratio 0.94 ± 0.13 (range, 0.57-1.18). The 1.5T studies produced less variability from investigator to investigator. Thirty-nine percent of contoured volumes were different by greater than 10%. At this institution, it was found that flair defined GTVs for high grade gliomas were on average smaller that at 3T. There was increased volume variability on 3T MR.

Purpose/Objective(s)We hypothesized that there is no difference in the peritumoral and tumor related signal abnormality used to define a radiotherapy GTV detected by 1.5 Tesla (T) versus 3T T2 FLAIR magnet resonance imaging (MRIs).Materials/MethodsA total of 11 patients with newly diagnosed, high grade-gliomas were enrolled in this IRB approved prospective trial. Prior to beginning radiotherapy, all patients underwent a 1.5T and 3T MR scans within a 24 hour period, with no treatment or steroid dose change between scans. Image processing and radiation planning was performed using radiation oncology software (iPlanImage 4.1, BrainLab). GTV was defined as the T2 FLAIR signal abnormality and segmentation of this volume was independently performed by 4 investigators: 2 radiation oncologists and 2 neurosurgeons on both the 1.5T and 3T studies. To decrease inherent biases, investigators contoured 1.5T and 3T MRs separately, with a minimum of 72 hours between contours, blinded to other contours. For each patient and investigator the volumes defined by FLAIR images at 1.5 and 3T were determined and the ratio of the volumes (GTV3T/GTV1.5T) were calculated. The mean volume ratios were calculated for each investigator as well as an overall average. To assess the consistency of contours from investigator to investigator, the standard deviations and range of the volumes amongst all investigators were determined for each patient at each field strength.ResultsThe volumes ratios for each investigator (GTV3T/GTV1.5T) were 0.83 ± 0.22 (range 0.37-1.03), 0.82 ± 0.26 (range 0.19-1.01), 0.91 ± 0.19 (range 0.37-1.14), and 0.98 ± 0.14 (range 0.66-1.18). One patient was clearly an outlier, with 3T volumes 0.19 to 0.66 that of the 1.5T volumes. The overall GTV3T/GTV1.5T ratio was 0.89 ± 0.21. Excluding the outlier produced an overall GTV3T/GTV1.5T ratio 0.94 ± 0.13 (range 0.57-1.18). The 1.5T studies produced less variability from investigator to investigator, with mean standard deviation of the volumes of 5.1% at 1.5T and 13.3% at 3T.ConclusionsAt this institution it was found that FLAIR defined GTVs for high-grade gliomas were on average 11% ± 20% smaller at 3T than at 1.5T, with increased volume variability. Further analyses will be performed to assess any impact radiation treatment planning by magnet strength might have on patterns of tumor recurrence. Purpose/Objective(s)We hypothesized that there is no difference in the peritumoral and tumor related signal abnormality used to define a radiotherapy GTV detected by 1.5 Tesla (T) versus 3T T2 FLAIR magnet resonance imaging (MRIs). We hypothesized that there is no difference in the peritumoral and tumor related signal abnormality used to define a radiotherapy GTV detected by 1.5 Tesla (T) versus 3T T2 FLAIR magnet resonance imaging (MRIs). Materials/MethodsA total of 11 patients with newly diagnosed, high grade-gliomas were enrolled in this IRB approved prospective trial. Prior to beginning radiotherapy, all patients underwent a 1.5T and 3T MR scans within a 24 hour period, with no treatment or steroid dose change between scans. Image processing and radiation planning was performed using radiation oncology software (iPlanImage 4.1, BrainLab). GTV was defined as the T2 FLAIR signal abnormality and segmentation of this volume was independently performed by 4 investigators: 2 radiation oncologists and 2 neurosurgeons on both the 1.5T and 3T studies. To decrease inherent biases, investigators contoured 1.5T and 3T MRs separately, with a minimum of 72 hours between contours, blinded to other contours. For each patient and investigator the volumes defined by FLAIR images at 1.5 and 3T were determined and the ratio of the volumes (GTV3T/GTV1.5T) were calculated. The mean volume ratios were calculated for each investigator as well as an overall average. To assess the consistency of contours from investigator to investigator, the standard deviations and range of the volumes amongst all investigators were determined for each patient at each field strength. A total of 11 patients with newly diagnosed, high grade-gliomas were enrolled in this IRB approved prospective trial. Prior to beginning radiotherapy, all patients underwent a 1.5T and 3T MR scans within a 24 hour period, with no treatment or steroid dose change between scans. Image processing and radiation planning was performed using radiation oncology software (iPlanImage 4.1, BrainLab). GTV was defined as the T2 FLAIR signal abnormality and segmentation of this volume was independently performed by 4 investigators: 2 radiation oncologists and 2 neurosurgeons on both the 1.5T and 3T studies. To decrease inherent biases, investigators contoured 1.5T and 3T MRs separately, with a minimum of 72 hours between contours, blinded to other contours. For each patient and investigator the volumes defined by FLAIR images at 1.5 and 3T were determined and the ratio of the volumes (GTV3T/GTV1.5T) were calculated. The mean volume ratios were calculated for each investigator as well as an overall average. To assess the consistency of contours from investigator to investigator, the standard deviations and range of the volumes amongst all investigators were determined for each patient at each field strength. ResultsThe volumes ratios for each investigator (GTV3T/GTV1.5T) were 0.83 ± 0.22 (range 0.37-1.03), 0.82 ± 0.26 (range 0.19-1.01), 0.91 ± 0.19 (range 0.37-1.14), and 0.98 ± 0.14 (range 0.66-1.18). One patient was clearly an outlier, with 3T volumes 0.19 to 0.66 that of the 1.5T volumes. The overall GTV3T/GTV1.5T ratio was 0.89 ± 0.21. Excluding the outlier produced an overall GTV3T/GTV1.5T ratio 0.94 ± 0.13 (range 0.57-1.18). The 1.5T studies produced less variability from investigator to investigator, with mean standard deviation of the volumes of 5.1% at 1.5T and 13.3% at 3T. The volumes ratios for each investigator (GTV3T/GTV1.5T) were 0.83 ± 0.22 (range 0.37-1.03), 0.82 ± 0.26 (range 0.19-1.01), 0.91 ± 0.19 (range 0.37-1.14), and 0.98 ± 0.14 (range 0.66-1.18). One patient was clearly an outlier, with 3T volumes 0.19 to 0.66 that of the 1.5T volumes. The overall GTV3T/GTV1.5T ratio was 0.89 ± 0.21. Excluding the outlier produced an overall GTV3T/GTV1.5T ratio 0.94 ± 0.13 (range 0.57-1.18). The 1.5T studies produced less variability from investigator to investigator, with mean standard deviation of the volumes of 5.1% at 1.5T and 13.3% at 3T. ConclusionsAt this institution it was found that FLAIR defined GTVs for high-grade gliomas were on average 11% ± 20% smaller at 3T than at 1.5T, with increased volume variability. Further analyses will be performed to assess any impact radiation treatment planning by magnet strength might have on patterns of tumor recurrence. At this institution it was found that FLAIR defined GTVs for high-grade gliomas were on average 11% ± 20% smaller at 3T than at 1.5T, with increased volume variability. Further analyses will be performed to assess any impact radiation treatment planning by magnet strength might have on patterns of tumor recurrence.

Purpose/Objective: To assess the outcome of patients in whom radiotherapy (RT) was not given, in order to determine if any patient subset might have omission of RT tested in future clinical trials. Materials/Methods: Seventy-two patients who remained on study and did not fail up to the time when RT would have begun were analyzed. Among these 72, RT omission was allowed per protocol in 24 who had second-look surgery (SLS) (20 with non-bladder/prostate (B/P) GU primaries, one with bladder dome, and three amputees with extremity primaries); these patients were included in this analysis. 904 CG III patients on IRS-III and -IV who did receive RT are reported for comparison but without tests of statistical significance. Primary endpoints were five-year total local failure (LF), failure-free survival (FFS), and overall survival (OS). Results: LF was not different overall (18% v 16%). However, non-B/P GU patients were infrequent in the RT cohort (3%) but comprised 46% (33/72) of the no RT cohort, and their relatively low LF skewed the overall LF rate. Examining each site group separately revealed apparently worse LF without RT, whereas FFS and OS were better in the no RT cohort for all site groups except those with other/PM/orbit/H&N primaries (TABLE). In the RT group, the effect of age (under 1 yr v 1 yr or older) was examined separately for GU and for all others. For GU patients, LF was 28% v 8%, FFS was 71% v 91%, and OS was 86% v 100%. For all others, LF 62% v 12%, FFS 37% v 66%, and OS 63% v 70%. Second-look surgery in the no RT group consisted of radical procedures (total or subtotal sacrifice of at least one organ, resulting in irreversible loss of function) in 21/72 (including 9 cystectomies, 8 hysterectomies, 6 vaginectomies, and 3 extremity amputations), resection in 22, biopsy in 16, and unknown in 6. No SLS was performed in 7 patients. Conclusions: Omission of RT in favor of SLS or no local therapy resulted in local failure rates higher than would be predicted for all primary sites. Radical surgery was used in 21/72 patients. Age under 1 year was also predictive of higher local failure risk. Nevertheless, overall survival in this highly selected population was not compromised, especially in non-B/P GU patients. The clinical features to permit RT omission cannot be fully determined in this analysis, supporting the current guidelines for SLS and RT dose reduction as recommended in IRS V. Tabled 1

Background. Although age < 1 year at diagnosis has been associated with a worse prognosis in rhabdomyosarcoma (RMS), the relationship of age at diagnosis to clinical presentation and outcome has not been evaluated carefully. We reviewed data from recent Intergroup Rhabdomyosarcoma Study Committee (later called Group, IRSG) trials to examine this relationship in order to estimate prognosis more accurately and further refine treatment. Procedure. We used data from IRS-III, -IV Pilot, and -IV (198397, N=2,343) to study the relationship of patient age with clinical features and prognosis in a large cohort of patients treated with contemporary therapy. Results. We showed that, after adjusting for important prognostic factors, age was an independent risk factor for treatment failure and patients could be classified into three failure-risk categories based on age (i.e., < 1 year; 1-9 years; > 10 years). Infants and adolescents were more likely to have unfavorable features, including alveolar or undifferentiated tumors and advanced Group and Stage, and also had significantly poorer failure-free survival (FFS) than did children aged 1-9 (53 and 51% vs. 72%, P < 0.001). Although there was a difference in FFS among age categories, there was no evidence that age influences outcome within the three categories. Conclusions. Since age relates independently to outcome after adjustment for known risk factors, it is likely that other factors, including perhaps patients' tolerance of protocol-specified therapy, explain this relationship. (c) 2003 Wiley-Liss, Inc.

Purpose/Objective: To evaluate the impact of RT parameters on cancer control outcomes (Local/regional failure (LF), event-free (EFS) and overall survival (OS)) for children with parameningeal rhabdomyosarcoma (PM-RMS) treated on IRSG protocols II to IV (including IRS IV pilot). Materials/Methods: RT quality was assessed by contemporary review of portal radiographs, simulation films, treatment plans and cross-sectional diagnostic imaging data for patients treated on IRSG protocols II through IV. The Quality Assurance Review Center (QARC) managed the RT quality control for the IRSG. Over the span of these clinical trials, RT guidelines evolved. After IRS-II initiation, the study was amended to require whole brain RT (WBRT) in all patients with PM-RMS with any evidence of intracranial extension (ICE), cranial nerve palsy (CNP) or cranial base bone erosion (CBBE) because of CNS failure in IRS I and early IRS-II patients. WBRT was eliminated on IRS-III (after 1987) for patients without ICE and eliminated entirely on IRS-IV. 595 patients with PM tumors were registered from 1978 to 1997. The majority (95%) had Group III disease. The median time from study entry to start of RT was 6 days. Protocol RT was to be 40-55 Gy in 1.8 Gy daily except on IRS-IV, where Group III patients were randomized to receive 50.4 Gy in 1.8 Gy daily vs 59.4 Gy in 1.1 Gy BID. The median radiation dose was 44 Gy for Group II patients and 53 Gy for Group III patients. Patients with CNP and/or CBBE with or without ICE were required to start radiotherapy at the time of study entry (day zero). Of the 595 patients reviewed, 385 (65%) had diagnostic imaging submitted to QARC for assessment of target volume coverage. Only 123 (21%) received WBRT, 49 (40%) of whom were treated on IRS-II. Coverage of the target volume based upon portal and simulation film review was judged as Good (>2 cm margin all directions), Fair (<2cm margin in two or fewer borders), or Poor (<2cm margin in more than two borders or shielding gross disease). Results: Table 1 lists the 5 year outcomes for LF, EFS, and OS. Based upon this contemporary review, LF was 15% with Good RT, 20% with Fair RT and 18% with Poor RT. There was no evidence that use of adequate WBRT affected LF or CNS relapse. Group III patients had more LF if they received <47.5 Gy and had large (>5cm) tumors (35%) compared to patients with who received <47.5 Gy with small tumors (18%) or >47.5 Gy with large (15%) or small (15%) tumors (p=.14). For patients with ICE, starting RT <2 weeks after study initiation (N=177) had 16% LF compared to 37% if started >2 weeks (N=19) (p=.07). Multivariate analysis of RT parameters and clinical factors demonstrates that dose is important in LF. ICE, CNP, CBBE, tumors >5cm and age >10 are unfavorable prognostic factors.Table 1Five year results of Local Failure, Event Free Survival and Overall Survival for patients with Parameningeal RhabdomyosarcomaIRS-II (N=165)IRS-III(N=122)IRS-IVP(N=115)IRS-IV(N=193)Local Failure20%20%12%18%p=0.23Event Free Survival61%72%74%72%p=0.37Overall Survival67%76%75%75%p=0.49 Open table in a new tab Conclusions: Although this contemporary review of technical parameters did not yield differences in outcome based upon treatment field design, the central quality assurance managed by QARC maintained a high standard of treatment quality. This review convincingly demonstrates that WBRT is unnecessary in PM-RMS. The current standard dose of 50.4 Gy for Group III patients is appropriate.

PURPOSE: The study goal was to improve outcome in children with rhabdomyosarcoma by comparing risk-based regimens of surgery, radiotherapy (RT) and chemotherapy. PATIENTS AND METHODS: Eight hundred eighty-three previously untreated eligible patients with nonmetastatic rhabdomyosarcoma entered the Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) (1991 to 1997) after surgery and were randomized treatment by primary tumor site, group (1 to 3), and stage (I to III). Failure-free survival (FFS) rates and survival were the end points used in comparisons between randomized groups and between patient subgroups treated on IRS-III and IRS-IV. Most patients were randomized to receive vincristine and dactinomycin (VA) and cyclophosphamide (VAC, n = 235), or VA and ifosfamide (VAI, n = 222), or vincristine, ifosfamide, and etoposide (VIE, n = 236). Patients with group 3 tumors were randomized to receive conventional RT (C-RT) versus hyperfractionated RT (HF-RT). RESULTS: Overall 3-year FFS and survival were 77% and 86%, respectively. Three-year FFS rates with VAC, VAI, and VIE were 75%, 77%, and 77%, respectively (P = .42). No significant difference in outcome was noted with HF-RT versus C-RT (P = .85 and P = .90, respectively). Overall, patients with embryonal tumors benefited from intensive three-drug chemotherapy in IRS-IV (3-year FFS, 83%). The improvement was seen for patients with stage I or stage II/III, group 1/2 disease, many of whom received VA chemotherapy on IRS-III. Patients with stage 2/3, group 3 disease had similar outcomes on IRS-III and IRS-IV. Three-year FFS for the nonrandomized patient subsets was 75% with renal abnormalities; 81% for paratesticular, group 1 cases; and 91% for group 1/2 orbit or eyelid tumors. Patients with paratesticular primaries had poorer outcomes if they were more than 10 years old (3-year FFS, 63% v 90%). Myelosuppression occurred in most patients, but toxic deaths occurred in less than 1%. CONCLUSION: VAC and VAI or VIE with surgery (with or without RT), are equally effective for patients with local or regional rhabdomyosarcoma and are more effective for embryonal tumors than therapies used previously. Younger patients with group 1 paratesticular embryonal tumors and all patients with group 1/2 orbit or eyelid tumors can usually be cured with VA chemotherapy along with postoperative RT for group 2 disease.

PURPOSE:To investigate the antitumor activity and toxicity of topotecan, used alone and in combination with conventional therapy, in patients with metastatic rhabdomyosarcoma (RMS).PATIENTS AND METHODS:Forty-eight patients younger than 21 years of age with newly diagnosed metastatic RMS received 2.0 to 2.4 mg/m(2) of topotecan intravenously daily for 5 days every 21 days before standard therapy. Two courses were given in the absence of progressive disease or excessive toxicity and response was assessed. Patients with at least a partial response (PR) to topotecan proceeded to therapy with alternating courses of vincristine 1.5 mg/m(2), dactinomycin 1.5 mg/m(2), and cyclophosphamide 2.2 g/m(2) (VAC) and vincristine 1.5 mg/m(2), topotecan 0.75 mg/m(2) daily x 5, and cyclophosphamide 250 mg/m(2) daily x 5. Patients who did not respond to topotecan received continuation therapy with VAC alone.RESULTS:The overall response rate to topotecan was 46% (complete response, 4%; partial response 42%). Unexpectedly, patients with alveolar RMS had a higher rate of response (65%) than those with embryonal RMS (28%; P: = .08). The most common grade 3 or 4 toxicities were neutropenia (67%), anemia (33%), thrombocytopenia (25%), and infection (21%). Two-year failure-free survival and survival estimates were 24% and 46%, respectively. Response to window therapy did not correlate with survival.CONCLUSION:The high response rate and acceptable toxicity profile of topotecan in children with advanced RMS support further evaluation of this agent in phase III trials. The superior responses in alveolar RMS are of interest.

PURPOSE: To report a patient recovering vision after three-dimensional conformal radiotherapy for optic nerve sheath meningioma.METHODS: Radiotherapy was delivered by a three-dimensional-conformal technique in 28-180 cGy fractions.RESULTS: Visual acuity improved from 20/200 to 20/30, and the:visual field defect resolved.CONCLUSION: Visual loss from optic nerve sheath meningioma can be reversed by three-dimensional conformal radiotherapy. (C) 2000 by Elsevier Science Inc. All rights reserved.

Purpose: A subset of 362 pediatric patients with rhabdomyosarcoma was selected from a total of 532 eligible IRS-II patients in Clinical Group III to assess the local and regional failure rates following radiotherapy and to determine patient, tumor, and treatment factors contributing to the risk for local and regional failure.Methods and Materials: The study population was selected from all eligible IRS-II Clinical Group III patients. Excluded patients were those with ''special pelvic'' primary sites whose protocol management restricted radiotherapy (n = 123), and those who were removed from the study before radiotherapy was to begin, or because it was omitted (n = 47). A binary recursive partitioning model was used to identify subgroups of the remaining 362 patients at risk of local or regional failure.Results: The local (only) failure rate was 17% (95% confidence interval, 13-21%), and the local (all) failure rate was 20% (95% confidence interval, 16-24%). The 5-year actuarial risk of local (all) failure was 22% (95% confidence interval, 18-27%). The risk of regional (nodal) failure was between 2% and 23%. Increasing tumor size predicted an increased local failure risk. Primary tumors located above the clavicle had a reduced risk of local failure. The binary recursive partitioning model identified a subset of patients at high risk of local failure. Those patients had primary tumors in the chest, pelvic region, extremity, or trunk, or tumors > 10 cm in diameter. Their local failure rate was 35% (compared to 15% for the remaining patients). The subset of patients at high risk for regional (nodal) failure had node involvement at diagnosis and a primary tumor originating at a site other than orbit, parameningeal, or trunk. Compliance with radiation treatment guidelines approached but did not achieve statistical significance as a predictive factor for local failure. By univariate analysis, factors not influencing local failure risk were age, race, gender, adenopathy, and histology.Conclusion: Radiation therapy and chemotherapy administered to Clinical Group III patients entered into the IRS-II protocol produced sustained local control in most cases. Knowledge of the factors which predict an increased risk of local or regional failure will facilitate the design of new treatment strategies. (C) 1997 Elsevier Science Inc.

PURPOSE:The purpose of this study was to determine the feasibility, toxicity, and early response of patients with clinical group III rhabdomyosarcoma (RMS) to a chemotherapy regimen of etoposide (ETOP), ifosfamide (IFOS), and vincristine (VCR) with hyperfractionated radiation therapy (XRT). PATIENTS AND METHODS:Sixty-eight patients aged < 21 years, previously untreated, with clinical group III RMS or undifferentiated sarcoma with normal organ function were eligible for this study. Chemotherapy was as follows: weeks 0-8: IFOS 1.8 g/m2/day X 5 days every 3 weeks X 3 (with mesna), ETOP 100 mg/m2/day X 5 days every 3 weeks X 3, and VCR 1.5 mg/m2/week X 9; weeks 9-16: hyperfractionated XRT (except patients with parameningeal tumors with meningeal extension, who received XRT on day 0), IFOS/mesna weeks 9, 12, 16, and VCR weeks 9, 10, 11, 12, 16; weeks 20-99; IFOS/mesna q 3 weeks X 2, ETOP q 3 weeks X 2, and VCR weekly X 6 weeks. Four drug cycles were repeated every 9 weeks, beginning at week 29. In January 1991, the duration of therapy was reduced to 12 courses due to emerging evidence of IFOS-induced renal tubular dysfunction. RESULTS:Of the 62 patients evaluable for response, 45 (73%) achieved a complete response. There were three fatal toxicities due to infection. Life-threatening neutropenia was seen in 55 of 60 patients, and life-threatening infections occurred in 27 of 60 patients. Twenty-five patients (42%) developed some degree of neurotoxicity from vincristine. Eleven patients (18%) developed nephrotoxicity, 7 cases of which were severe; 6 of the 11 patients who developed nephrotoxicity were < 2 years old. CONCLUSIONS:This pilot study had toxicity and response rates comparable to the other two Intergroup Rhabdomyosarcoma Study (IRS)-IV pilot trials of vincristine-actinomycin-cyclophosphamide and vincristine-actinomycin-ifosfamide and is, therefore, being evaluated in the current IRS randomized trial. Due to the high incidence of life-threatening neutropenia and infections, the use of growth factors is now routine. Five of 11 patients who developed nephrotoxicity did so after more than eight courses of IFOS; therefore, the current randomized trial limits IFOS to a total of eight courses.

Purpose: The Intergroup Rhabdomyosarcoma Study (IRS) Group initiated a pilot study (IRS TV-P) of hyperfractionated radiation (HF XRT) with chemotherapy to test the feasibility and toxicity of this combined modality approach in children with localized but nonresected (group LU) and metastatic (group Iv) rhabdomyosarcoma.Methods and Materials: Using the linear quadratic equation, and an alpha/beta ratio of 10 Gy for acute reacting tumor effect and 3 Gy for late reacting normal tissue effect, a HF XRT protocol was developed giving a total radiation dose of 59.4 Gy, in 1.10 Gy fractions, twice daily at 6-8 h intervals. All patients received chemotherapy in addition to irradiation. The radiation scheme was calculated to increase the biologically effective dose to the tumor by 10% without increasing late effects, when compared to a conventional schedule of 50.4 Gy in 1.8 Gy daily fractions. This protocol also was predicted to cause an increase in acute normal tissue effects.Results: Four hundred forty-nine children age 21 years and younger were eligible for the hyperfractionated radiation study of whom 297 had Group III disease and 152 had Group IV disease. A total of 117 patients were excluded from the feasibility and toxicity analysis because of progressive disease or death prior to scheduled irradiation, surgical resection, major protocol violation, treatment with brachytherapy, or missing data. Thus, 332 children were evaluable for the HF XRT protocol. Twenty-eight of the 332 (8%) were given conventional radiation because of physician preference or young age. Twenty of the 332 (6%) were not irradiated because of young age, anesthesia, or transportation problems. All nonirradiated children were less than or equal to 3 years of age, Thus, 284 children, 86% of the evaluable population, received HF XRT. The radiation dose, number of fractions, number of days, and interfractional interval were scored as appropriate in 93% of cases. Review of radiation portals revealed that in 230 of 284 cases (81%) the radiation fields were appropriate, as per protocol. Thus, the HF XRT was feasible treatment in a multiinstitutional study. Analysis of toxicity revealed that 152 of 204 (75%) of Group III and 52 of 80 (65%) of Group IV patients experienced severe or life-threatening toxicity, explained by the addition of chemotherapy with the radiation. The majority of this toxicity was hematopoietic. Observed organ toxicity, which was potentially explained by the radiation treatment, was greatest at the end of radiation, and improved at the 6-week and 3-month evaluation periods. There were no deaths attributed to radiation toxicity and no instance of toxicity that required alteration of the radiation protocol. Thus, the treatment was not associated with toxicity that was considered excessive or unusual.Conclusion: The IRS IV-P study confirms that HF XRT combined with chemotherapy is both feasible and tolerable in children with rhabdomyosarcoma. A prospective randomized trial is underway to test its efficacy as compared to conventional radiation among children also receiving concurrent chemotherapy for rhabdomyosarcoma.

The objective of this research was to determine whether the frequencies of chromosomally defective germ cells increased with age in male laboratory mice. Two types of chromosomal abnormalities were characterized: (1) testicular spermatid aneuploidy (TSA) as measured by a new method of multi-color fluorescence in situ hybridization (FISH) with DNA probes specific for mouse chromosomes X, Y and 8, and (2) spermatid micronucleus (SMN) analyses using anti-kinetochore antibodies. B6C3F1 mice (aged 22.5 to 30.5 months, heavier than controls but otherwise in good health) showed significant approximately 2.0 fold increases in the aneuploidy phenotypes X-X-8, Y-Y-8, 8-8-X and 8-8-Y with the greatest effects appearing in animals aged greater than 28 months. No age effect was observed, however, in X-Y-8 hyperhaploidy. Major age-related increases were seen in Y-Y-8 and X-X-8 hyperhaploidies suggesting that advanced paternal age is associated primarily with meiosis II rather than meiosis I disjunction errors. A approximately 5 fold increase was also found in the frequency of micronucleated spermatids in aged mice when compared with young controls. All micronuclei detected in the aged animals lacked kinetochore labeling, suggesting that they either did not contain intact chromosomes or the chromosomes lacked detectable kinetochores. The findings of the TSA and SMN assays are consistent with meiotic or premeiotic effects of advanced age on germ cell chromosomes, but there were differences in the age dependencies of aneuploidy and micronuclei. In summary, advanced paternal age may be a risk factor for chromosomal abnormalities (both aneuploidy and structural abnormalities) in male germ cells.